The overall goal of this research is to develop stereoselective methods for the formation of sterically congested carbon-carbon bonds in order to provide rapid, efficient, and selective routes to biologically active molecules. These types of bonds are found in numerous natural product targets. The structurally related class of tetramic acid macrolactams, characterized by a polysubstituted bicyclo (3.3.0 core and a tetramic acid moiety connected within a macrolactam, are accessible by this methodology. They are of fundamental interest since members of this class exhibit a diverse biological activity profile. Cylindramide exhibits cytotoxicity against B16 melanoma cells. Geodin A is a potent nematocidal agent. Alteramide A shows cytotoxicity against murine leukemia P388 cells, murine lymphoma L1210 cells, and the human epidermoid carcinoma KB cells in vitro. Discodermide inhibits the in vitro proliferation of cultured murine P388 leukemia cells and has some antifungal activity. Aburatubolactam A was found to inhibit superoxide anion generation while aburatubolactam C induces apoptosis. The central approach of this research is to convert chiral vinyl ethers into the corresponding carbon-carbon bonds with retention of stereochemistry. This strategy takes advantage of the multitude of ways to control carbon-oxygen bond stereochemistry to translate it into carbon-carbon bond stereochemistry. Specifically, the goals of this research are: 1) develop and explore the scope of the stereoretentive O to C rearrangement of vinyl acetals; 2) apply this insight to the development of a general vinyl ether O to C rearrangement and investigate its limits; 3) explore new methods for the stereodefined generation of vinyl ethers in order to expand the scope of the stereoretentive O to C rearrangement of vinyl acetals and ethers; 4) extend these studies to the stereoretentive replacement of chiral ethers with other nucleophiles; 5) develop a mechanistic understanding of these reactions; 6) couple the stereoretentive O to C rearrangement with a subsequent transformation to facilitate the rapid assembly of oligopyrans relevant to the ladder toxin family of natural products; 7) implement these methods in the stereoselective synthesis of tetramic acid macrolactams such as cylindramide.